Pyridine derivatives

Abstract

A compound of formula I wherein X represents an optionally halo-substituted (C 2-4 )alkynylene group bonded via vicinal unsaturated carbon atoms.

What is claimed is:  
     
       1. A compound of formula I                    
       wherein 
       X represents an optionally halo-substituted (C 2-4 )alkynylene group bonded via vicinal unsaturated carbon atoms,  
       R 1  is (C 1-4 ) alkyl, (C 1-4 )alkoxy, hydroxy(C 1-4 )alkyl, cyano, ethynyl, carboxy, (C 1-4 )alkoxycarbonyl, di(C 1-4 )alkylamino, (C 1-6 )alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl,  
       R 2  is hydrogen, hydroxy, (C 1-4 ) alkyl, hydroxy (C 1-4 ) alkyl, (C 1-4 ) alkoxy, carboxy, (C 2-5 )alkanoyloxy, (C 1-4 ) alkoxycarbonyl, di(C 1-4 )alkylamino(C 1-4 )alkanoyl, di(C 1-4 )alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,  
       R 3  is hydrogen, (C 2-4 ) alkyl, carboxy, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylcarbamoyl, hydroxy(C 1-4 )alkyl, di(C 1-4 )alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy,  
       R 4  is hydrogen, hydroxy, (C 1-4 )alkoxy, carboxy, (C 2-5 )alkanoyloxy, (C 1-4 )alkoxycarbonyl, amino(C 1-4 )alkoxy, di(C 1-4 )alkylamino(C 1-4 )alkoxy, di(C 1-4 )alkylamino(C 1-4 )alkyl, carboxy (C 1-4 )alkylcarbonyl, (C 1-4 )alkoxycarbonyl(C 1-4 )alkoxy, hydroxy(C 1-4 )alkyl, di(C 1-4 )alkylamino(C 1-4 )alkoxy, m-hydroxy-p-azidophenylcarbonylamino(C 1-4 )alkoxy, and  
       R 5  is a group of formula                    
        wherein  
       R a  and R b  independently are hydrogen, hydroxy, halogen, nitro, cyano, carboxy, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy(C 1-4 )alkyl, (C 1-4 )alkoxycarbonyl, (C 2-7 )alkanoyl, (C 2-5 )alkanoyloxy, (C 2-5 )alkanoyloxy(C 1-4 )alkyl, trifluoromethyl, trifluoromethoxy, trimethylsilylethynyl, (C 2-5 )alkynyl, amino, azido, amino (C 1-4 )alkoxy, (C 2-5 )alkanoylamino(C 1-4 )alkoxy, (C 1-4 )alkylamino(C 1-4 )alkoxy, di(C 1-4 )alkylamino(C 1-4 )alkoxy, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C 2-5 )alkanoylamino, benzylcarbonylamino, (C 1-4 )alkylamino carbonylamino, (C 1-4 )alkoxycarbonyl-aminocarbonylamino or (C 1-4 )alkylsulfonyl, R c  is hydrogen, fluorine, chlorine, bromine, hydroxy, (C 1-4 )alkyl, (C 2-5 )alkanoyloxy, (C 1-4 )alkoxy or cyano, and  
       R d  is hydrogen, halogen or (C 1-4 )alkyl, provided that in compounds wherein R 2 , R 3  and R 4  are hydrogen, when R 1  is methyl, R 5  is different from phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in form of a pharmaceutically acceptable salt.  
     
     
       2. A compound of formula I according to  claim 1 , wherein 
       X represents an optionally halo-substituted (C 2-4 ) alkynylene group bonded via vicinal unsaturated carbon atoms,  
       R 1  is (C 1-4 ) alkyl, (C 1-4 )alkoxy, cyano, ethynyl or di(C 1-4 )alkylamino,  
       R 2  is hydrogen, hydroxy, carboxy, (C 1-4 ) alkoxycarbonyl, di(C 1-4 )alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,  
       R 3  is hydrogen, (C 1-4 ) alkyl, carboxy, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylcarbamoyl, hydroxy(C 1-4 )alkyl, di(C 1-4 )alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy,  
       R 4  is hydrogen, hydroxy, carboxy, (C 2-5 )alkanoyloxy, (C 1-4 )alkoxycarbonyl, amino (C 1-4 )alkoxy, di(C 1-4 )alkylamino(C 1-4 )alkoxy, di(C 2-4 )alkylamino(C 1-4 )alkyl or hydroxy(C 1-4 )alkyl, and  
       R 5  is a group of formula                    
       wherein 
       R a  and R b  independently are hydrogen, halogen, nitro, cyano, (C 1-4 )alkyl, (C 1-4 )alkoxy, trifluoromethyl, trifluoromethoxy or (C 2-5 )alkynyl,  
       R c  is hydrogen, fluorine, chlorine, bromine, hydroxy, (C 1-4 )alkyl, (C 2-5 )alkanoyloxy, (C 1-4 )alkoxy or cyano, and  
       R d  is hydrogen, halogen or (C 1-4 )alkyl,  
       provided that in compounds wherein R 2 , R 3  and R 4  are hydrogen, when R 1  is methyl, R 5  is different from phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in form of a pharmaceutically acceptable salt. 
     
     
       3. A compound according to  claim 1  wherein X is ethynylene, in free form or in form of a pharmaceutically acceptable salt. 
     
     
       4. A compound according to  claim 1  wherein R 5  is different from optionally substituted phenyl and X is ethynylene, in free form or in form of a pharmaceutically acceptable salt. 
     
     
       5. A compound according to  claim 1  wherein R 5  is optionally substituted pyridin-3-yl and X is ethynylene, in free form or in form of a pharmaceutically acceptable salt. 
     
     
       6. A compound which is 2-[2-(Pyridin-3-yl)ethynyl]-6-methyl-pyridine in free form or in form of a pharmaceutically acceptable form. 
     
     
       7. A method of treating disorders which are mediated fully or in part by mGluR1 or mGluR5, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I                    
       wherein 
       X represents an optionally halo-substituted lower alkenylene or alkynylene group bonded via vicinal unsaturated carbon atoms or an azo (—N═N—) group,  
       R 1  denotes hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkyl-amino, piperidino, carboxy, esterified carboxy, amidated carboxy, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-lower-alkyl-N-phenylcarbamoyl, lower alkoxy, halo-lower alkyl or halo-lower alkoxy,  
       R 2  denotes hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,  
       R 3  represents hydrogen, lower alkyl, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl, hydroxy-lower alkyl, di-lower alkyl-aminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy,  
       R 4  represents hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, unsubstituted or hydroxy-substituted lower alkyleneamino-lower alkyl, lower alkoxy, lower alkanoyloxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, phthalimido-lower alkoxy, unsubstituted or hydroxy- or 2-oxo-imidazolidin-1-yl-substituted lower alkyleneamino-lower alkoxy, carboxy, esterified or amidated carboxy, carboxy-lower-alkoxy or esterified carboxy-lower-alkoxy, and  
       R 5  denotes an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from lower alkyl, halo, halo-lower alkyl, halo-lower alkoxy, lower alkenyl, lower alkynyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkynyl, hydroxy, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, amino-, lower alkylamino-, lower alkanoylamino- or N-lower alkyl-N-lower alkanoylamino-lower alkoxy, unsubstituted or lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted phenoxy, unsubstituted or lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkoxy, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, carboxy-lower alkylamino, esterified carboxy-lower alkylamino, amidated carboxy-lower alkylamino, phosphono-lower alkylamino, esterified phosphono-lower alkylamino, nitro, amino, lower alkylamino, di-lower alkylamino, acylamino, N-acyl-N-lower alkylamino, phenylamino, phenyl-lower alkylamino, cycloalkyl-lower alkylamino or heteroaryl-lower alkylamino each of which may be unsubstituted or lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted,  
       in free form or in the form of a photoaffinity ligand, a radioactive marker, an N-oxide or a pharmaceutically acceptable salt.  
     
     
       8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to  claim 1 , in free form or in the form of a pharmaceutically acceptable salt.